In recent years, selective serotonin reuptake inhibitors (SSRIs) have started to be used for treating depression and other central nervous system disorders, noteworthy among which are fluoxetine, citalopram, sertraline and paroxetine. They all have different chemical structures, which helps to explain their different metabolic and pharmacokinetic profiles.
The present invention relates to a number of new 4-substituted piperidines having an aryloxy functionality and potently inhibiting serotonin and/or noradrenaline reuptake, as a result of their high affinity for their neuronal transporters.
Potential therapeutic applications of these compounds are treatment of nervous bulimia, alcohol addiction, anxiety, obsessive-compulsive disorders, panic, pain, pre-menstrual syndrome and social phobia, as well as migraine prophylaxis. Bibliography also describes other piperidine derivatives with aryloxy functionality as potential antidepressants, albeit with a chemical nature differing essentially from those claimed herein, since the piperidine is substituted at the 3-position. That is for instance the case of such compounds as 3-[(2-methoxyphenoxy)phenyl]methyl-piperidine 1 (Melloni, P., Carniel, G., Della Torre, A., Bonsignalari, A., Buonamici, M., Pozzi, O., Ricciardi, S., Rossi, A. C. Eur. J. Med. Chem. Chim. Ther. 1984, 3, 235-242; Melloni, P., Della Torre, A., De Munari, S., Meroni, M., Tonani, R. Gazetta Chimica Italiana 1985, 115, 159-163) and 3-[(phenoxy)phenyl]methyl-piperidine 2 (FR 2,010,615 CA73; 66442j; GB 1,203,149 CA73: 120509b). In these compounds, the substitution of the piperidine ring at the 3-position results in an additional chiral centre. The presence of the two chiral centres results in diastereomeric mixtures, which is the form in which the preparation of these compounds 
has been described. The preparation and/or isolation of pure enantiomers is not described in any case. However, the compounds claimed in the present specification possess a single chiral centre, since they have the piperidine ring substituted at the 4-position. They have been prepared as racemic mixtures and as pure enantiomers, using synthetic methods differing from those used in preparing 1 and 2.
Moreover, other piperidine derivatives having aryloxy functionality and the piperidine ring substituted at the 4-position have been described as potential antidepressants (formulae 3 and 4). Thus, in the case of 3 type compounds (JP 96 40,999 CA124: 343333n), 
the aryloxy group is directly joined to the piperidine ring, whereas in the 4 type compounds (JP 96 40,999 CA124: 343333n) said group is joined to the piperidine ring through a methylene group which has no further substitutions. The compounds described herein differ largely from those, since they have the aryloxy group joined to the piperidine ring through a methylene group wherein, in all cases, one of the methylene group hydrogens is substituted by an aryl group, substituted or not, as defined hereinafter. These compounds are therefore structurally different from the 3 and 4 types and the synthetic methodology used in preparing the same is also absolutely different.
The new 4-substitude piperidines described in the present invention are represented by general formula (I), in which groups R1 and R2 are non-substituted aryl radicals or aryl radicals mono- or poly-substituted with halogen (fluorine, chlorine, bromine, iodine), alkyl, alkoxy, cyano, trifluoromethoxy, trifluoromethyl, benzoyl, phenyl, nitro, amino, aminoalkyl, aminoaryl and carbonylamino. 
The compounds of general formula (I) have an asymmetric centre and have been prepared as racemic mixtures and as pure enantiomers. The present invention includes all optical isomers of the compounds of general formula (I) and racemic mixtures thereof. The present invention also comprises the pharmaceutically acceptable salts of these compounds with inorganic acids (such as: hydrochloric, hydrobromic, nitric, sulphuric and phosphoric) and with organic acids (such as: acetic, fumaric, tartaric, oxalic, citric, p-toluenesulphonic and methanosulphonic).
The racemic compounds of general formula (I) were prepared using well-known synthetic methods starting with the compounds of general formula (II).
Formation of the alklarylether group was carried out using the Mitsunobu reaction (Mitsunobu, O. Synthesis 1981, 1; Hughes, D. L. Organic Reactions 42, 335) with phenols R2xe2x80x94OH, in which R2 is an aryl radical, substituted or not, as described for general formula (I), and the compounds of general formula (II), in which R1 is an aryl radical, substituted or not, as described for general formula (I), and R3 is hydrogen or R4, which is an alkoxycarbonyl radical, preferably ethoxycarbonyl and t-butoxycarbonyl. 
The alkylarylether group was also prepared using an aromatic nucleophilic substitution reaction (Berglund, R. A. Org. Proc. Res. Dev. 1997 1, 328-330) with the compounds of general formula (II) defined above, and the fluorinated derivatives R2xe2x80x94F, in which R2 is an aryl radical mono- or poly-substituted with halogen (fluorine, chlorine, bromine, iodine), alkyl, alkoxy, cyano, trifluoromethoxy, trifluoromethyl, benzoyl, phenyl, nitro, amino, aminoalkyl, aminoaryl and carbonylamino. The compounds of general formula (II) were prepared using conventional synthetic methods, starting with the compounds of general formula (III) (Duncan, R. L., Helsley, G. C., Welstead, W. J., DaVanzo, J. P., Funderburk, W. H., Lunsford, C. D. J. Med. Chem. 1970, 13 (1), 1), in which R5 is an acetyl radical, ethoxycarbonyl and R6 is cyano or carboxy. 
The compounds of general formula (III) defined above were transformed into the compounds of general formula (IV), in which R1 is an aryl radical, substituted or not, 
as described for the compounds of general formula (I), and R7 is hydrogen, acetyl or R4, which is an alkoxycarbonyl radical, preferably ethoxycarbonyl and t-butoxycarbonyl. Such transformation was made using two reaction types: a) a Friedel-Crafts reaction of the acid chlorides derived from the compounds of general formula (III), in which R5 is an acetyl or ethoxycarbonyl and R6 is carboxy (Duncan, R. L., Helsley, G. C., Welstead, W. J., DaVanzo, J. P., Funderburk, W. H., Lunsford, C. D. J. Med. Chem. 1970, 13 (1), 1) with benzene or conveniently functionalised derivatives thereof; or b) a Grignard reactive addition reaction, prepared from conveniently functionalised aryl halides, to compounds of general formula (III) in which R5 is acetyl, ethoxycarbonyi or t-butoxycarbonyl and R6 is cyano (Duncan, R. L., Helsley, G. C., Welstead, W. J., DaVanzo, J. P., Funderburk, W. H., Lunsford, C. D. J. Med Chem. 1970, 13 (1), 1). Reduction of the compounds of general formula (IV) described provides the general formula (II) alcohols defined above.
The enantiomers composing the racemic mixtures of general formula (I) were obtained using two different pathways: a) resolution of the corresponding racemic mixture by split crystallisation of the diastereomeric salts prepared with chiral acids (D or L-dibenzoyltartaric, D or L-tartaric, D or L-di-p-toluyltartaric and D or L-mandelic) and b) enantioselective synthesis. In the latter case, the enantiomers of general formula (I) were obtained by reacting phenols R2xe2x80x94OH or the fluorinated aromatic derivatives R2xe2x80x94F defined above, with the enantiomers of the general formula (II) alcohols, as described for the racemic mixtures of general formula (I). In the enantiomers of the general formula (II) alcohols, R1 is an aryl radical, substituted or not, as defined for the compounds of general formula (I), and R3 is hydrogen or R4, which is an alkoxycarbonyl radical, preferably ethoxycarbonyl and t-butoxycarbonyl. The enantiomers of the general formula (II) alcohols defined above were obtained by enantioselective reduction (arnachandran, P. V., Teodorovic, A. V., Rangaishenvi, M. V., Brown, H. C. J. Org. Chem. 1992, 57, 2379-2386) of the compounds of general formula (IV) (Duncan, R. L., Helsley, G. C., Welstead, W. J., DaVanzo, J. P., Funderburk, W. H., Lunsford, C. D. J. Med. Chem. 1970, 13 (1), 1), in which R1 is an aryl radical, substituted or not, as defined for the compounds of general formula (I), and R7 is hydrogen or R4, defined above.
The pharmacological activity of the compounds of general formula (I) was determnined-using well-established in vitro and in vivo pharmacological processes. The affinity of the compounds for the serotonin reuptake receptors (5HT) was evaluated in fuill rat cerebral cortex, using P[3H]-paroxetine as radioligand (Habert, E., Graham, D., Tahraoui, L., Claustre, Y., Langer, S. Z. Eur J. Pharmacol. 1985, 118, 107-114) yielding Ki values ranging between 0.5 and 500 nmol/l. The affinity of the compounds for noradrenaline (NA) reuptake receptors was evaluated in full rat cerebral cortex, using [3H]-nisoxetine as radioligand (Tejani-Butt, S. M., J. Pharmacol. Exp. Ther. 1992, 260, 1, 427-436), yielding Ki values ranging between 1 and 500 nmol/l.
The compounds with Ki ranging between 0.5 and 40 nmol/l, for one of the transporters or for both, displayed an excellent antidepressant activity in the three models when administered within the 1 to 30 mg/Kg range orally, intraperitoneally or subcutaneously. See Example 9.
The following examples illustrate the scope of the present invention, which is not howsoever limited to such examples.